The present invention relates to drug delivery, and in particular to pharmaceutical compositions and methods for the improved solubilization of both triglycerides and surfactants and improved delivery of therapeutic agents, particularly polysaccharide drugs, including low molecular weight heparin. The invention has utility in the fields of pharmaceutical formulation, pharmacology and medicine.
A wide variety of therapeutic agents are conventionally formulated in oil/water emulsion systems. These conventional emulsions take advantage of the increased solubility of many therapeutic agents in oils (triglycerides). Thus, one conventional approach is to solubilize a therapeutic agent in a bioacceptable triglyceride solvent, such as a digestible vegetable oil, and disperse this oil phase in an aqueous medium. The dispersion may be stabilized by emulsifying agents and provided in emulsion form. Alternatively, the therapeutic agent can be provided in a water-free formulation, with an aqueous dispersion being formed in vivo in the gastrointestinal environment. The properties of these oil-based formulations are determined by such factors as the size of the triglyceride/therapeutic agent colloidal particles and the presence or absence of surfactant additives.
In simplest form, a triglyceride-containing formulation suitable for delivering therapeutic agents through an aqueous environment is an oil-in-water emulsion. Such emulsions contain the therapeutic agent solubilized in an oil phase that is dispersed in an aqueous environment with the aid of a surfactant. The surfactant may be present in the oil-based formulation itself, or may be a compound provided in the gastrointestinal system, such as bile salts, which are known to be in vivo emulsifying agents. The colloidal oil particle sizes are relatively large, ranging from several hundred nanometers to several microns in diameter, in a broad particle size distribution. Since the particle sizes are on the order of or greater than the wavelength range of visible light, such emulsions, when prepared in an emulsion dosage form, are visibly xe2x80x9ccloudyxe2x80x9d or xe2x80x9cmilkyxe2x80x9d to the naked eye.
Although conventional triglyceride-based pharmaceutical compositions are useful in solubilizing and delivering some therapeutic agents, such compositions are subject to a number of significant limitations and disadvantages. Emulsions are thermodynamically unstable, and colloidal emulsion particles will spontaneously agglomerate, eventually leading to complete phase separation. The tendency to agglomerate and phase separate presents problems of storage and handling, and increases the likelihood that pharmaceutical emulsions initially properly prepared will be in a less optimal, less effective, and poorly-characterized state upon ultimate administration to a patient. Uncharacterized degradation is particularly disadvantageous, since increased particle size slows the rate of transport of the colloidal particle and digestion of the oil component, and hence the rate and extent of absorption of the therapeutic agent. These problems lead to poorly characterized and potentially harmful changes in the effective dosage received by the patient. Moreover, changes in colloidal emulsion particle size are also believed to render absorption more sensitive to and dependent upon conditions in the gastrointestinal tract, such as pH, enzyme activity, bile components, and stomach contents. Such uncertainty in the rate and extent of ultimate absorption of the therapeutic agent severely compromises the medical professional""s ability to safely administer therapeutically effective dosages. In addition, when such compositions are administered parenterally, the presence of large particles can block blood capillaries, further compromising patient safety.
A further disadvantage of conventional triglyceride-containing compositions is the dependence of therapeutic agent absorption on the rate and extent of lipolysis. Although colloidal emulsion particles can transport therapeutic agents through the aqueous environment of the gastrointestinal tract, ultimately the triglyceride must be digested and the therapeutic agent must be released in order to be absorbed through the intestinal mucosa. The triglyceride carrier is emulsified by bile salts and hydrolyzed, primarily by pancreatic lipase. The rate and extent of lipolysis, however, are dependent upon several factors that are difficult to adequately control. For example, the amount and rate of bile salt secretion affect the lipolysis of the triglycerides, and the bile salt secretion can vary with stomach contents, with metabolic abnormalities, and with functional changes of the liver, bile ducts, gall bladder and intestine. Lipase availability in patients with decreased pancreatic secretory function, such as cystic fibrosis or chronic pancreatitis, may be undesirably low, resulting in a slow and incomplete triglyceride lipolysis. The activity of lipase is pH dependent, with deactivation occurring at about pH 3, so that the lipolysis rate will vary with stomach contents, and may be insufficient in patients with gastric acid hyper-secretion. Moreover, certain surfactants commonly used in the preparation of pharmaceutical emulsions, such as polyethoxylated castor oils, may themselves act as inhibitors of lipolysis. Although recent work suggests that certain surfactant combinations, when used in combination with digestible oils in emulsion preparations, can substantially decrease the lipolysis-inhibiting effect of some common pharmaceutical surfactants (see, U.S. Pat. No. 5,645,856), such formulations are still subject to the other disadvantages of pharmaceutical emulsions and triglyceride-based formulations.
Yet another approach is based on formation of xe2x80x9cmicroemulsions.xe2x80x9d Like an emulsion, a microemulsion is a liquid dispersion of oil in water, stabilized by surfactants. Conventional microemulsions, however, present several safety and efficiency problems. The amount of triglyceride that can be solubilized in a conventional microemulsion is generally quite small, resulting in a poor loading capacity. In order to solubilize significant amounts of triglycerides, large amounts of hydrophilic surfactant and/or solvents must be used. These high concentrations of hydrophilic surfactant and solvents raise questions of safety, since the levels of hydrophilic surfactant and solvent needed can approach or exceed bioacceptable levels.
Thus, conventional triglyceride-containing formulations suffer from limitations and safety concerns including, for example, instability of the formulation, dependence on lipolysis and poor loading capacity of the therapeutic agent. Triglyceride-containing formulations incorporating a therapeutic agent, in particular a polysaccharide drug, that do not suffer from these and other limitations and safety concerns are desired.
Administration of one particular class of therapeutic agents, the polysaccharide drugs, is severely hampered by the permeation barrier imposed by the intestinal epithelial cell membrane as well as the junctional structure between the epithelial cells. In addition, chemical degradation in the acidic environment of the stomach, enzymatic inactivation, and binding or interference by mucous and other contents of the gastrointestinal (GI) tract can also contribute to the reduced availability of polysaccharide drugs in the GI tract for absorption. As a result, the administration of polysaccharide drugs frequently calls for invasive approaches such as subcutaneous or intravenous injection, resulting in severe restrictions in clinical use and problems with patient compliance.
Heparin is a polysaccharide drug of particular interest and importance because it is a potent anticoagulant drug widely used in the prevention and treatment of thrombosis. It decreases the rate of coagulation by increasing the rate at which antithrombin (also termed xe2x80x9cheparin cofactorxe2x80x9d or xe2x80x9cantithrombin IIIxe2x80x9d) inhibits activated coagulation factors, particularly thrombin, a key enzyme in the coagulation cascade. Heparin is a glycosaminoglycan present in the secretory granules of mast cells, and is characterized as a polymer of alternating D-glucuronic acid and N-acetyl-D-glucosamine residues (Bourin et al. (1993), xe2x80x9cGlycosaminoglycans and the Regulation of Blood Coagulation,xe2x80x9d Biochem. J. 289:313-330). Heparinoidsxe2x80x94derivatives, analogs, fragments, salts, esters, etc. of heparin or heparin like glycosaminoglycan such as chrondroitin, dermatan sulfate, sulfomucopolysaccharide, mesoglycan, sulodexide, etc.xe2x80x94are also of paramount interest as anticoagulants.
Among all the heparins and heparinoids, low molecular weight heparin is of particular interest from a clinical standpoint. The potential advantages of low molecular weight heparin over unfractionated heparin include are numerous. For example, it has been suggested that low molecular weight heparin may be associated with a reduced risk of bleeding complications, possibly due to its more specific action on clotting factor Xa and relatively low action on factor IIa. In addition, low molecular weight heparin has a longer half-life so dosing frequency can be reduced. Because low molecular weight heparin exhibits reduced binding to platelets, the incidence of thrombocytopenia is substantially reduced. Furthermore, the likelihood of bone loss is reduced because low molecular weight heparin tends to bind less strongly to osteoblasts. See Hirsch et al. (1998), xe2x80x9cHeparin and Low-Molecular-Weight Heparin.xe2x80x9d Chest 114:489S-510S.
Administration of a polysaccharide drug in a triglyceride-containing formulation would overcome some problems such as chemical degradation and enzymatic degradation that are associated with the administration of this class of drug. U.S. Pat. No. 5,626,869 to Nyqvist et al. describes pharmaceutical compositions containing heparin or heparin fragments in a defined lipid system of at least two lipid components. The particles in the described formulations, however, can vary considerably. Such variation in particle sizes results in a milky or cloudy dispersion as some particles in the formulations ostensibly have sizes corresponding to the wavelength of light. In addition, U.S. Pat. No. 5,744,155 to Friedman et al. describes oil-in-water emulsions containing a drug such as a low molecular weight heparin. The described emulsions contain particles having diameters of from 10 nm to 600 nm. Again, the formulations will be milky or cloudy as the particle sizes contained in the described formulations overlap the wavelengths of visible light (400 nm to 700 nm).
Clearly, then, there is a need in the art for a triglyceride-containing formulation for the administration of a polysaccharide drug, such as heparin, heparinoids, and particularly low molecular weight heparin, wherein the formulation contains a therapeutically effective amount of the polysaccharide drug, and the dosage formulation is chemically and physically stable, as evidenced, for example, by a clear dispersion.
It is therefore an object of the present invention to provide pharmaceutical compositions capable of solubilizing therapeutically effective amounts of therapeutic agents.
It is a further objection of the invention to provide pharmaceutical compositions, wherein the therapeutic agent is a polysaccharide drug.
It is another object of the invention to provide triglyceride-containing pharmaceutical compositions that are homogeneous and thermodynamically stable.
It is still another object of the invention to provide pharmaceutical compositions of a therapeutic agent that have decreased dependence upon lipolysis for bioabsorption.
It is yet another object of the invention to provide pharmaceutical compositions capable of increasing the rate and/or extent of bioabsorption of co-administered therapeutic agents.
It is a further object of the invention to provide pharmaceutical compositions and methods for the prevention of blood coagulation and treatment of thrombosis.
In accordance with these and other objects and features, the present invention provides pharmaceutical compositions for improved solubilization of triglycerides, and improved delivery of therapeutic agents. It has been surprisingly found that pharmaceutical compositions containing significant amounts of triglycerides can be formed without the disadvantages of conventional triglyceride-containing compositions by using a combination of surfactants and triglycerides in amounts such that when the pharmaceutical composition is mixed with an aqueous medium, a clear aqueous dispersion is formed. Such compositions can be co-administered with a therapeutic agent to increase the rate and/or extend of bioabsorption of the therapeutic agent, or can be provided with a therapeutic agent in the preconcentrate composition or in the diluent solution.
In one embodiment, the present invention relates to pharmaceutical compositions having a carrier and a therapeutic agent, e.g., polysaccharide drug, the carrier including a triglyceride and at least two surfactants, at least one of which is hydrophilic. The triglyceride and surfactants are present in amounts such that upon mixing with an aqueous medium in an aqueous medium to carrier ratio of about 100:1 by weight, either in vitro or in vivo, the carrier forms a clear aqueous dispersion. In one aspect of this embodiment, the aqueous dispersion has an absorbance of less than about 0.3 at 400 nm. In another aspect of this embodiment, the aqueous dispersion has an average particle size of less than about 200 nm. In yet another aspect of this embodiment, the carrier is capable of containing more triglyceride than can be solubilized in a clear aqueous dispersion having only one surfactant, the surfactant being hydrophilic.
In another embodiment, the present invention relates to pharmaceutical compositions having a carrier and polysaccharide drug, the carrier including a triglyceride, at least one hydrophilic surfactant, and at least one hydrophobic surfactant. The triglyceride and surfactants are present in amounts such that upon mixing with an aqueous medium in an aqueous medium to carrier ratio of about 100:1 by weight, either in vitro or in vivo, the carrier forms a clear aqueous dispersion. In a particular aspect of this embodiment, the carrier is capable of containing more triglyceride than can be solubilized in a clear aqueous dispersion having a hydrophilic surfactant but not having a hydrophobic surfactant.
In another embodiment, the present invention relates to pharmaceutical compositions having therapeutic agent and a carrier, the carrier including a triglyceride, at least one hydrophilic surfactant, and at least one hydrophobic surfactant. The triglyceride and surfactants are present in amounts such that upon mixing with an aqueous medium in an aqueous medium to carrier ratio of about 100:1 by weight, either in vitro or in vivo, the carrier forms a clear aqueous dispersion. In a particular aspect of this embodiment, the at least one hydrophobic surfactant is present in an amount greater than the amount of the at least one hydrophobic surfactant that remains solubilized in an aqueous dispersion of the carrier having only the at least one hydrophobic surfactant and hydrophilic surfactant without the triglyceride.
In another embodiment, the present invention relates to dosage forms comprising the pharmaceutical compositions described herein. The dosage forms may be processed by techniques selected from the group consisting of lyophilization, encapsulation, extruding, compression, melting, molding, spraying, coating, comminution, mixing, homogenization, sonciation, granulation, and combinations thereof. Dosage forms include, but are not limited, those selected from the group consisting of pills, capsules, caplets, tablets, granules, beads, powders, solutions, suspensions, emulsions, creams, ointments, lotions, suppositories, sprays, aerosols, pastes, gels, drops, douches, ovules, wafers, troches, cachets, syrups and elixirs.
In another embodiment, the invention relates to methods of treating an animal, e.g., a mammalian patient such as a human patient, with a therapeutic agent, e.g., a polysaccharide drug, the method involving providing a dosage form of a pharmaceutical composition having a carrier as described herein, providing the polysaccharide drug, and administering the dosage form to the animal. In one particular aspect of this embodiment, the polysaccharide drug is administered simultaneously, e.g., either as a part of the composition or as part of a separate and distinct composition. In another aspect of this embodiment, the polysaccharide drug is administered sequentially, e.g., either the polysaccharide drug is administered first followed by administration of the composition, or the composition is first followed by administration of the polysaccharide drug.
In another embodiment, the invention relates to the administration of a combination of therapeutic agents, e.g., a low molecular weight (LMW) heparin in combination with an anticoagulant, platelet inhibitor, and/or fibrinolytic agent, in a single dosage form or in separate dosage forms. Such combinations provide several benefits to patients as will be discussed below. Preferred combinations include: LMW heparin with one or more anticoagulants, e.g., warfarin sodium, dipyridamole, or a combination thereof; LMW heparin with one or more platelet inhibitors, e.g., aspirin, hirudin, cilostazol, ticlidopine, clopidrogel, abciximab, eptifitabide, bivalirudin, or combination thereof; and LMW heparin with a fibrinolytic agent, e.g., unfractionated heparin, r-tPA, or combinations thereof.
In another embodiment, the present invention relates to methods of increasing the amount of hydrophobic surfactant that can be solubilized in a clear aqueous dispersion, by providing a composition including carrier having a triglyceride, at least one hydrophilic surfactant, and one hydrophobic surfactant, and dispersing the composition in an aqueous medium so that a clear aqueous dispersion is formed. Within the clear aqueous dispersion, the hydrophobic surfactant is present in an amount greater than the amount of the hydrophobic surfactant that remains solubilized in an aqueous dispersion of the carrier having only the at least one hydrophobic surfactant and hydrophilic surfactant without the triglyceride.
In another embodiment, the present invention relates to methods of treating an animal, e.g., a mammalian patient, with a therapeutic drug, the method comprising providing an initial dosage form of a pharmaceutical composition having a therapeutic agent and a carrier comprising a triglyceride, at least one hydrophilic surfactant, and at least one hydrophobic surfactant, and administering the dosage form to the animal. The triglyceride and surfactants are present in amounts such that upon mixing with an aqueous medium in an aqueous medium to carrier ratio of about 100:1 by weight, either in vitro or in vivo, the carrier forms a clear aqueous dispersion. The at least one hydrophobic surfactant is present in an amount greater than the amount of the at least one hydrophobic surfactant that remains solubilized in an aqueous dispersion of the carrier having only the at least one hydrophobic surfactant and hydrophilic surfactant without the triglyceride. The primary therapeutic agent may be present in the initial dosage form or may be present in a second dosage form. Similarly, additional therapeutic agents may be present in the initial dosage form or may be present in a second dosage form, independent of the dosage form containing the primary therapeutic agent.
In another embodiment, the present invention relates to a pharmaceutical composition comprising an oil soluble vitamin and a carrier comprising a triglyceride, at least one hydrophilic surfactant, and at least one hydrophobic surfactant. The triglyceride and surfactants are present in amounts such that upon mixing with an aqueous medium in an aqueous medium to carrier ratio of about 100:1 by weight, either in vitro or in vivo, the carrier forms a clear aqueous dispersion.
In another embodiment, the present invention relates to a method for increasing the loading capacity of a pharmaceutical composition comprising the steps of: providing a pharmaceutical composition comprised of (a) a carrier comprising a triglyceride and a first surfactant, and (b) a therapeutically effective amount of a polysaccharide drug; and adding an absorption-enhancing amount of a second surfactant to the pharmaceutical composition, the second surfactant comprising a hydrophilic surfactant, wherein the absorption enhancing amount is effective to increase the loading capacity of the capacity of the pharmaceutical composition.
These and other objects and features of the present invention will become more fully apparent from the following description and appended claims, or may be learned by the practice of the invention as set forth hereinafter.